tbuckley/cabot-search huggingface dataset:
Abstract 684: Nanovaccine displaying immunodominant T cell epitopes of fibroblast activation protein is effective against desmoplastic tumors
Authors: Hocheol Shin, Yujin Kim, Sangyong Jon
Journal: Cancer Research (2023)

Abstract Cancer-associated fibroblasts (CAFs), which are dominant cell types in the tumor microenvironment (TME), support tumor growth by secreting cytokines and forming an extracellular matrix (ECM) that hampers penetration of chemical and biological therapeutics within the tumor and thereby limits their therapeutic efficacy. Here, we report a cancer nanovaccine targeting fibroblast activation protein alpha (FAP)-expressing CAFs as a potential pan-tumor vaccine. We predicted immunodominant FAP-specific epitope peptides and selected two candidate peptides after in vitro and in vivo screening for immunogenicity and antitumor efficacy. Next, we developed a nanoparticle-based vaccine that displays the two selected epitope peptides on the surface of lipid nanoparticles encapsulating CpG adjuvant (FAPPEP-SLNPs). Immunization with one of two FAPPEP-SLNP nanovaccines led to considerable growth inhibition of various tumors, including desmoplastic tumors, by depleting FAP+ CAFs and thereby reducing ECM production in the TME while causing little appreciable adverse effects. Furthermore, when combined with a chemotherapeutic drug, the FAPPEP-SLNP nanovaccine increased drug accumulation and resulted in a synergistic antitumor efficacy far better than that of each corresponding monotherapy. These findings suggest that our FAPPEP-SLNP nanovaccine has potential for use as an “off-the-shelf” pan-tumor vaccine applicable to a variety of tumors and may be a suitable platform for use in various combination therapies. Citation Format: Hocheol Shin, Yujin Kim, Sangyong Jon. Nanovaccine displaying immunodominant T cell epitopes of fibroblast activation protein is effective against desmoplastic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 684.
Abstract 5817: LKB1 overcomes RAS pathway-mediated loss of epithelial integrity
Authors: Topi A. Tervonen, Shishir M. Pant, Johanna Englund, Juha Klefström
Journal: Cancer Research (2023)

Abstract Oncogenic RAS pathway disassembles cell-cell and cell-basement membrane junctions, thus promoting epithelial cell motility and invasion. To find tumor proteomic changes responsible for the disrupting effects of RAS on epithelial integrity, we explored cBioportal cell line proteomics data across all cancer types for correlations between oncogenic KRAS or HRAS mutations and possible regulators of epithelial integrity. We found inverse correlation between these RAS mutations and tumor suppressor LKB1 protein levels in a cohort where LKB1 was not inactivated by a mutation. Furthermore, LKB1 protein levels were also positively correlated with NF2 protein (a negative regulator of RAS) in human breast tumors and inversely correlated with c-RAF (RAS effector) activating phosphorylation at serine 338 in breast cancer cell lines. We sought to functionally clarify the relationship between RAS pathway and LKB1, finding that an ectopic constitutive or inducible expression of HRASV12 downregulates LKB1 protein in mammary epithelial MCF10A cells and HMEC-hTERT cells. Furthermore, RAS-mutant MCF10A cells regained LKB1 protein levels upon treatment with MEK/ERK inhibitors. We establish that the RAS-mediated downregulation of LKB1 protein occurs through proteasomal activity. LKB1 reconstituted MCF10A-HRASV12 (RAS-LKB1) cells displayed restored desmoplakin, γ-catenin and E-cadherin pericellular immunostaining pattern in monolayer cultures, suggesting restoration of desmosomes and adherence junctions. We also cultured RAS-LKB1 cells in 3D egg-white and observe restoration of E-cadherin, γ-catenin, α6-integrin, and laminin-332, indicating a rescue of epithelial integrity in 3D context. Our findings suggest that LKB1 rescues mutant RAS-mediated disruption of cell-cell and cell-basement membrane junctions and general epithelial integrity. Our current aim is to define how LKB1 suppresses RAS mediated disruption of breast epithelial integrity, that is expected to shed new light into early stages of tumor invasion and uncover novel therapeutic opportunities via restoration of LKB1. Citation Format: Topi A. Tervonen, Shishir M. Pant, Johanna Englund, Juha Klefström. LKB1 overcomes RAS pathway-mediated loss of epithelial integrity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5817.
Abstract 6232: Ulipristal acetate, a selective progesterone receptor modulator, induces cell death via inhibition of STAT3/CCL2 signaling pathway in uterine sarcoma
Authors: Jae Ryoung Hwang, Young-Jae Cho, Ji-Yoon Ryu, Ju-Yeon Choi, Jung-Joo Choi, Jeong-Won Lee
Journal: Cancer Research (2023)

Abstract Purpose: Ulipristal acetate (UPA) is used for the treatment of uterine leiomyoma as a selective progesterone receptor modulator. Until now, there has been no experimental research on the effect of UPA on uterine sarcoma. In this study, we examined the efficacy of UPA in uterine sarcoma with in vitro and in vivo animal models. Experimental Design: The cytotoxicity of UPA was determined in uterine sarcoma cell lines (MES-SA, SK-UT-1, and SK-LMS-1) by MTT and caspase-3 activity assays. A migration assay was done using a Transwell chamber, and MMP-2 was measured with its specific ELISA kit. Apoptotic genes and signaling pathways affected by UPA were analyzed by complementary DNA (cDNA) microarray of uterine sarcoma cell lines and western blot, respectively. The in vivo efficacy of UPA was examined in uterine sarcoma cell line- and patient-derived xenograft mice models. Results: UPA inhibited cell growth and increased apoptosis in cell lines including uterine sarcoma (MES-SA) and leiomyosarcoma (SK-UT-1 and SK-LMS-1) in a dose-dependent manner. UPA also inhibited cell migration and the expression of MMP-2. cDNA microarray analysis revealed that CCL2 was commonly down-regulated by UPA in investigated cell lines. The UPA-mediated inhibition of CCL2 expression was confirmed by ELISA. The phosphorylation and the total expression of STAT3, downstream from the CCL2 signaling pathway, was also inhibited by UPA. We also found that UPA reduced cell growth and increased caspase-3 activity in primary culture cells from leiomyosarcoma patient-derived xenografts (PDX-C). Moreover, we found that STAT3/CCL2 inhibition by UPA was independent of the expression of progesterone receptor. In vivo studies with MES-SA and SK-UT-1 cell line-derived xenografts and a PDX model with leiomyosarcoma demonstrated that UPA significantly decreased tumor growth. Conclusions: UPA had significant anti-tumor effects in uterine sarcoma through the STAT3/CCL2 signaling pathway and might be a potential therapeutic agent to treat this disease. Citation Format: Jae Ryoung Hwang, Young-Jae Cho, Ji-Yoon Ryu, Ju-Yeon Choi, Jung-Joo Choi, Jeong-Won Lee. Ulipristal acetate, a selective progesterone receptor modulator, induces cell death via inhibition of STAT3/CCL2 signaling pathway in uterine sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6232.
Abstract 1888: IAE0972, A novel EGFR/IL10 immunocytokine of monovalent anti-EGFR antibody fused with IL10 homodimer
Authors: Liusong Yin, Xiaoling Jiang, Chongbing Wu, Zi Chen
Journal: Cancer Research (2023)

Abstract Exhaustion of immune cells in the tumor microenvironment has been found and confirmed in many tumor cases, accounting for the major problems of current PD1/L1-oriented immunotherapy. There are two types of exhausted T cells present in the tumor microenvironment: progenitor exhausted T cells and terminally exhausted T cells. Data from various mouse syngeneic tumor models suggest that the dominance of progenitor exhausted T cells will be replaced by terminally exhausted T cells as the tumor progresses. The PD1/PDL1 antibodies mainly act on progenitor exhausted T cells and can develop acquired resistance as terminally exhausted T cells become the dominant cells in the tumor microenvironment. Recently, there are studies demonstrating that IL10 can restore the oxidative phosphorylation metabolism of terminally exhausted T cells and restore their potent killing activities of tumor cells. We therefore designed IAE0972, a novel EGFR/IL10 immunocytokine to solve the problems of immune cell exhaustion in current immunotherapy. It is a monovalent anti-EGFR antibody fused with IL10 homodimer. The anti-EGFR antibody can specifically enrich IAE0972 in tumor microenvironment, so that IL10 can reinvigorate antigen specific CD8+ T cells and facilitate its proliferation, while preserving the tumor cell proliferation inhibition activities of EGFR antibody. The design of monovalent form anti-EGFR antibody can also avoid the skin toxicity problem. In this study, we studied the target binding activity, CD8+ T cell activation activity and cancer cell proliferation inhibition activity of IAE0972. We also observed a much higher anti-tumor efficacy of IAE0972 in a MC38 syngeneic tumor model compared with that of Cetuximab. In addition, the molecule has a very good safety profile with MTD over 6 mg/kg and no skin toxicities, which is about 300-fold higher than that of cytokine drugs. In summary, IAE0972 is an innovative EGFR/IL10 immunocytokine with robust preclinical anti-tumor efficacy and favorable safety profile, which has the potential to address acquired resistance of current immunotherapy. IAE0972 is the first EGFR/IL10 immunocytokine with IND approval from both FDA and NMPA. The indications of IAE0972 include colorectal cancer, head and neck squamous cell carcinoma, squamous non-small cell lung cancer, and other EGFR positive tumors. A Phase I/IIa clinical trial to evaluate the safety, tolerability and preliminary efficacy of IAE0972 in patients with locally advanced or metastatic malignant tumors is on-going (NCT05396339). Citation Format: Liusong Yin, Xiaoling Jiang, Chongbing Wu, Zi Chen. IAE0972, A novel EGFR/IL10 immunocytokine of monovalent anti-EGFR antibody fused with IL10 homodimer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1888.
Abstract 2453: Olfactomedin 4 downregulation enhances MYC-signaling in human benign prostate cells and the Olfm4 mouse models
Authors: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Griffin P. Rodgers
Journal: Cancer Research (2023)

Abstract Prostate cancer is the most diagnosed solid tumor and the second leading cause of cancer related death in American men. We have reported previously that OLFM4 gene expression was reduced or lost during prostate cancer progression due to frequent genetic deletion and hypermethylation of the OLFM4 gene promoter region. To investigate OLFM4 gene biological functions and molecular mechanisms underlying prostate cancer progression, we have established OLFM4 knock out RWPE1 cells and Olfm4 knock out mouse model. Functionally, OLFM4-knockout RWPE1 cells exhibited enhanced proliferation of the stem/progenitor-like cell population and abnormal differentiation. Bulk-cell RNA sequencing analysis pinpointed that MYC expression was enhanced in the OLFM4-knockout RWPE1 cells compared with OLFM4-wild cells. Molecular and signaling pathway studies revealed an increase in the WNT/APC/MYC signaling pathway gene signature and MYC target genes that regulate multiple biological processes in OLFM4-knockout RWPE1 cells and Olfm4-knock out mouse models. To test the function of the MYC gene in RWPE1 cells, we used (+)-JQ1, an MYC inhibitor, in both 2D and 3D culture models and found that (+)-JQ1 substantially inhibited the proliferation of OLFM4-knockout GFP reporter RWPE1 cells compared with OLFM4-W RWPE1 cells in both types of cultures. We further studied MYC inhibitors using organoid culture for Olfm4-/-/TRAMP mouse prostate tumors. These results suggest that OLFM4-negative prostate cancer is more sensitive to MYC inhibitor’s therapeutic approaches. Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Griffin P. Rodgers. Olfactomedin 4 downregulation enhances MYC-signaling in human benign prostate cells and the Olfm4 mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2453.
Abstract 71: Melanoma alters the bone marrow immune composition in an age-related manner
Authors: Alexis Erasta Carey, Yash Chhabra, Ethan Black, Murilo Ramos Rocha, Mitchell Fane, Vania Wang, Daniel Zabransky, Gloria Bravante, Laura Hueser, Ashani Weeraratna
Journal: Cancer Research (2023)

Abstract Melanoma accounts for the most skin cancer-related deaths in the United States. As patients age, anti-tumor responses decline, making age a negative independent prognostic factor of overall survival in melanoma. Despite advances in immunotherapeutic modalities, there remains a subset of patients who do not benefit from these treatments. Understanding cancer and age-related changes to immune cell development in the bone marrow can improve patient outcomes. We hypothesize that during aging, the bone marrow niche is reshaped, driving precursor cells to become immunosuppressive. This ultimately decreases the anti-tumor response to melanoma due to the skewing of hematopoiesis to yield decreased immune function. In order to tackle this hypothesis, flow cytometry was used to analyze immune compositional changes in the bone marrow of mice challenged with melanoma. Our preliminary data suggests that when melanoma is present in the skin, there are changes to the bone marrow niche, such as an increase in total myeloid cells. Specifically, in the bone marrow of aged tumor-bearing mice, we see a decrease in Ly6C+Ly6G+ granulocytic progenitor cells and an increase in Ly6C+Ly6G- monocytic progenitor cells compared to the bone marrow of young tumor-bearing mice. We predict that the secretome of the aged bone marrow niche will impact immune cell development by producing more immature myeloid cells that can travel to the tumor site. We also saw an increase in the proportion of CD4+ T-cells in the aged bone marrow when melanoma is present. Thus, there appears to be a shift in cell populations in the aged bone marrow niche when the mice are burdened with melanoma. As a future direction, we plan to investigate the role of the aged bone marrow niche and its secretome on the effectiveness of immunotherapies, such as anti-PD-1. These insights could lead to improved outcomes for elderly patients with melanoma. Citation Format: Alexis Erasta Carey, Yash Chhabra, Ethan Black, Murilo Ramos Rocha, Mitchell Fane, Vania Wang, Daniel Zabransky, Gloria Bravante, Laura Hueser, Ashani Weeraratna. Melanoma alters the bone marrow immune composition in an age-related manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 71.
Abstract 6722: RNAScope <i>in situ</i> hybridization as a novel approach for the spatiotemporal assessment of RD3 mRNA expression in neuroblastoma
Authors: Dinesh Babu Somasundaram, Sheeja Aravindan, Zhongxin Yu, Ashley Baker, Natarajan Aravindan
Journal: Cancer Research (2023)

Abstract Our recent investigations unveiled the transcriptional and translational loss of Retinal degeneration Protein 3 in neuroblastomas (NB) when compared to the healthy adult and fetal tissues. Further, our preclinical studies with patient derived cellular systems and mouse model of high-risk NB (HR-NB) demonstrated that RD3 loss orchestrates disease progression. More importantly, we defined the therapy pressure driven acquired loss of RD3 in neuroblastomas, its crucial function in the evolution of progressive disease (PD), and further defined the prognostic and predictive significance of RD3 loss in NB. In this study, we investigated the use of RNAScope as a sensitive and specific method for the evaluation of spatiotemporal RD3 transcriptional loss in NB. We investigated the expression of RD3 mRNA in FFPE NB (n = 100) tissues utilizing RNAScope with custom archived RD3 specific probes comparing it with the matched RD3 protein (IHC) expression patterns. With positive (PPIB) and negative (DapB) controls in place, our results displayed definite and specific RD3 mRNA expression in NB. We observed a statistically significant association of RD3 mRNA loss to the disease progression and poor clinical outcomes. Further, we observed significant correlation to the loss of RD3 transcription to the evolution of progressive disease. More importantly, the expression gradients of RD3 mRNA observed with RNAScope assay (compared in terms of no treatment vs progressive disease, primary vs metastatic disease, relapsed vs no relapse, favorable to unfavorable disease) illustrate the concordance with the RD3 IHC outcomes. Our results provide a reference basis for better RD3 mRNA readouts in NB, and more importantly identify the technically sound, adaptable (high throughput/single event, manual/automatic) RNAScope in situ hybridization assay as an alternate approach to detect spatiotemporal expression of RD3 mRNA. Together, the results provide a new, descriptive, and efficient platform, RNAScope for assessing spatiotemporal RD3 mRNA expression that could better inform disease prognosis and therapy response in children with NB. Funding: This work was partially or in full, funded by Department of Defense DoD-CA210339 and Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-045. Citation Format: Dinesh Babu Somasundaram, Sheeja Aravindan, Zhongxin Yu, Ashley Baker, Natarajan Aravindan. RNAScope in situ hybridization as a novel approach for the spatiotemporal assessment of RD3 mRNA expression in neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6722.
Abstract 34: A clinically-relevant orthotopic endometrial carcinosarcoma mouse model using human patient-derived organoids
Authors: Arielle Katcher, Charlie Chung, Megan Gorman, Brian Yueh, Scott Lyons, Joseph Merrill, Libia Garcia, Marina Frimer, Gary L. Goldberg, Semir Beyaz
Journal: Cancer Research (2023)

Abstract Uterine carcinosarcoma (CS) is a rare but aggressive endometrial malignancy. Like the other subtypes of endometrial cancer, the incidence of CS has been increasing and it is projected to continue to rise. Additionally, there is racial disparity seen in African American women diagnosed with CS. African American women have an increased incidence of CS compared to other racial/ethnic groups. They also have an overall increased mortality related to endometrial cancer. Compared to other histologic subtypes of endometrial cancer, CS remains rare and understudied on a molecular and cellular basis. It remains under-represented in clinical trials. Therefore, the current therapies available for CS are extrapolated from those treatments used in the other subtypes of endometrial cancer. There is a paucity of data surrounding targeted therapies for CS resulting in worse outcomes for patients who are diagnosed with this aggressive and lethal cancer. We have developed a clinically relevant, orthotopic CS murine injection model by injecting human CS patient-derived organoids (PDO) from diverse ancestries into the endometrium of immunocompromised mice. Tumor progression in the mice was monitored with physical examination, PET/CT scan, contrast enhanced CT scan, and ultrasound. The tumor was established after three months and was visualized using various imaging techniques. The mice were sacrificed and the diagnosis of invasive CS was confirmed by macroscopic, histologic and genomic analyses. Our orthotopic CS PDO transplantation model has many potential applications for studying tumor biology and the response to treatment for CS in the pre-clinical setting. This may help identify targeted therapy for CS and potentially advance to Phase 1 human clinical trials. Citation Format: Arielle Katcher, Charlie Chung, Megan Gorman, Brian Yueh, Scott Lyons, Joseph Merrill, Libia Garcia, Marina Frimer, Gary L. Goldberg, Semir Beyaz. A clinically-relevant orthotopic endometrial carcinosarcoma mouse model using human patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 34.
Abstract 4970: TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors
Authors: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Matthew R. Tonini, Brian Haines, Alan Huang, Kevin M. Cottrell
Journal: Cancer Research (2023)

Abstract MTAP deletions occur in 10-15% of all human cancers, which provides one of the largest precision oncology patient populations. MTA-cooperative PRMT5 inhibitors leverage the well-characterized synthetic lethal relationship between PRMT5 inhibition and MTAP deletion. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors. TNG462 is an investigational stage MTA-cooperative PRMT5 inhibitor with significantly enhanced potency, selectivity, and extended target coverage designed to be a best-in-class treatment for patients with MTAP-deleted cancer. In vitro, TNG462 is 45X selective for MTAP-deleted cancer cell lines over isogenic MTAP WT cell lines and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. Oral administration of TNG462 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in cell line- and patient-derived xenograft models representative of clinically relevant histologies. Preclinical data suggest a low risk for drug-drug interactions, supporting clinical combination strategies. With enhanced potency and selectivity for MTAP-deleted cancer cells and improved pharmacokinetic properties to extend target coverage, TNG462 has the potential for broader and deeper clinical activity in MTAP-deleted solid tumors than the MTA-cooperative PRMT5 currently being evaluated in clinical trials. Citation Format: Kimberly J. Briggs, Alice Tsai, Minjie Zhang, Matthew R. Tonini, Brian Haines, Alan Huang, Kevin M. Cottrell. TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4970.